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Since the arrival of clade 2.3.4.4b avian influenza A(H5N1) in North America in late 2021, frequent mammal spillover events have occurred in a diverse range of species, including 1 human [...]

Three classes of direct-acting antivirals targeting the influenza virus matrix protein 2 (M2) ion channel, neuraminidase (NA), or polymerase cap-dependent endonuclease (CEN) are approved to treat influenza in many countries [...]

Mpox is caused by infection with monkeypox vi rus (MPXV). Phylogenomically and clinically, clades I and II can be distinguished; clade II has 2 subcodes, Ha and IIb (1). In [...]

Highly pathogenic avian influenza (HPAI) viruses pose a threat to wild birds and poultry globally, and HPAI H5N1 viruses are of even greater concern because of their frequent spillover into [...]

Chronic wasting disease (CWD) is a member of the prion family of fatal, infectious neurodegenerative diseases. CWD affects cervids, such as moose, elk, and several species of deer, across much [...]

Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG., Introduction Diffuse midline gliomas (DMGs) with H3K27M mutation (histone H3 lysine 27 replaced with methionine) are diffusely infiltrating glial neoplasms affecting midline structures of the CNS (1). DMG is one [...]

Cardiomyocyte sarcomeres contain localized ribosomes, but the factors responsible for their localization and the significance of localized translation are unknown. Using proximity labeling, we identified ribosomal protein SA (RPSA) as a Z-line protein. In cultured cardiomyocytes, the loss of RPSA led to impaired local protein translation and reduced sarcomere integrity. By employing CAS9-expressing mice, along with adeno-associated viruses expressing CRE recombinase and single-guide RNAs targeting Rpsa, we knocked out Rpsa in vivo and observed mislocalization of ribosomes and diminished local translation. These genetic mosaic mice with Rpsa knockout in a subset of cardiomyocytes developed dilated cardiomyopathy, featuring atrophy of RPSA-deficient cardiomyocytes, compensatory hypertrophy of unaffected cardiomyocytes, left ventricular dilation, and impaired contractile function. We demonstrated that RPSA C-terminal domain is sufficient for localization to the Z-lines and that if the microtubule network is disrupted RPSA loses its sarcomeric localization. These findings highlight RPSA as a ribosomal factor essential for ribosome localization to the Z-line, facilitating local translation and sarcomere maintenance., Introduction Local translation has several benefits over diffuse or unlocalized protein production. Importantly, it allows protein synthesis closer to the site of action, is more economic, may prevent protein aggregation, [...]

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similarly to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through combined effects on histone methylation and RNA [N.sup.6]- methyladenosine. The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high-L-2HG kidney cancers demonstrate reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high-L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors., Introduction Oncometabolites are small molecules that aberrantly accumulate within tumor cells. These small molecules can have either tumor-promoting or -suppressive effects, indicating that their impact on tumor biology is highly [...]

AbstractBladder cancer (BC) has shown a significant global health concern with distinct pathological, genetic, and epigenetic characteristics. Its prevalence is influenced by various risk factors, including age, gender, and genetic predisposition. This study investigates the association between BC and the Sirtuin 1 (SIRT1) gene polymorphism rs369274325 in the Turkish population. Genomic DNA was isolated from peripheral blood samples and genotyping of rs369274325 polymorphism in SIRT 1 was investigated in 200 individuals (in 100 Turkish bladder cancer patients and 100 healthy individuals as the control group.) by real-time PCR. Demographic information, smoking and alcohol consumption status was analyzed by statistical analysis. Statistical analysis was performed by Pearson’s Chi-square test. Smoking and alcohol consumption were significantly higher in BC patients compared to controls (p < 0.00018 and p < 0.0001, respectively). The genotypic distribution of SIRT1 rs369274325 did not show a significant difference between BC patients and controls (p = 0.5550). BC, influenced by genetic and environmental factors, has been linked to various gene mutations. SIRT1, involved in diverse physiological processes, is proposed to play a role in BC. However, our study did not find a significant association between SIRT1 rs369274325 polymorphism and BC in the Turkish population. [ABSTRACT FROM AUTHOR]